Psoriatic arthritis (PsA) is distinctive amongst the inflammatory/autoimmune joint diseases in that its onset is commonly preceded by cutaneous psoriasis (PsC). There is a major unmet need for predictive biomarkers to determine which of the ~25% of psoriasis patients will develop PsA. Moreover, PsC and PsA exhibit significant life-threatening co-morbidity, notably from cardiovascular disease. Over the past eight years, we have collected 634 PsA patients at Michigan, 545 of whom have already been subjected to genome-wide association studies (GWAS). The International Psoriatic Arthritis Research Team (IPART) has collected DNA samples from 1,215 PsA patients, 1,062 of which have already been subjected to GWAS. Essentially all of these PsA samples already have extensive clinical follow-up (mean 6.7 years). Meta-analysis of existing GWAS and Immunochip data for psoriasis has increased the number of known European-origin psoriasis loci to at least 32, and our recently completed GWAS of 1,442 PsA cases vs. 1,433 normal controls reveals a strong MHC Class I / III association signal distinct from HLA-Cw6 as well as genome- wide significance for multiple non-MHC loci including IL12B, TNFAIP3, TNIP1, and TYK2, and TRAF3IP2 . However, these signals account for only a relatively small fraction of the heritability of PsA, likely due a least in part to the existence of rare disease-predisposing variants. Therefore, to further dissec the genetics and the biology of, we propose the following specific aims: (1) To maintain and expand our longitudinal clinical resource by (a) supporting critical core elements of the current IPART resource, (b) expanding the Michigan longitudinal cohort under the IPART protocol and (c) utilizing social networking to increase sample size via patient self-report; and (d) validating this resource in IPART subjects. (2) To identify rare genetic susceptibility variants for PsA and PsC, making use of an innovative exome variation microarray developed from 1000 Genomes Project sequencing data to genotype 4,450 PsA cases, 3,600 PsC cases, and 11,800 normal controls. (3) To develop biomarkers for PsA development, disease subtypes, drug responsiveness, and co-morbidities in PsV patients. This will be accomplished by RNA isolation and RNASeq transcriptome analysis of (a) blood samples stored at study entry, which will be paired with additional blood and skin samples from incident PsA cases at the onset of PsA development; (b) a cross- sectional sample of blood and skin from 70 additional definite PsC cases and 70 definite PsA cases; and (c) correlation of genetic and genomic data with (i) physician-assessed and patient-reported responses to biologics targeting the TNF and IL-23/IL-17 axes, (ii) axial vs. peripheral PsA and nail involvement, and (iii) systemic co-morbidities including obesity and cardiovascular disease. RELEVANCE: PsA is a major health problem in the United States. The mechanisms that predispose patients to PsA vs. PsC are unknown. The proposed research will utilize the power of genome-wide association studies, transcriptome analysis, and the largest longitudinal resource of PsA in the world to address a major gap in our mechanistic understanding of the causes of PsA and its associated co-morbidities. The results of this research are also likely to be relevant to other autoimmune diseases. PUBLIC HEALTH RELEVANCE: PsA is a major health problem in the United States. The mechanisms that predispose patients to PsA vs. PsC are unknown. The proposed research will utilize the power of genome-wide association studies, transcriptome analysis, and the largest longitudinal resource of PsA in the world to address a major gap in our mechanistic understanding of the causes of PsA and its associated co-morbidities. The results of this research are also likely to be relevant to other autoimmune diseases.